Transport mechanisms in parasitic nematodes

寄生线虫的转运机制

• 批准号: 2777-2006
• 负责人: Prichard, Roger
• 金额: $ 6.25万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2006
• 资助国家: 加拿大
• 起止时间: 2006-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=340346
• 关键词: Transport; mechanisms; parasitic; nematodes

Parasitic nematodes cause disease, loss of production and death in farm animals requiring the use of expensive control measures using anthelmintic drugs. Virtually all anthelmintics target transport mechanisms in nematodes, indicating that these transport mechanisms represent unique targets in nematodes. For example, anthelmintics such as ivermectin, opens unique chloride channels in nematodes, causing muscle paralysis. However, membrane proteins, such as P-glycoproteins (Pgps), may regulate the concentration of anthelmintics at their sites of action. Understanding the functioning of these transport systems will advance our knowledge of nematode cellular physiology and the mechanisms of drug action and resistance. The objectives of the proposed research will be to further elucidate details of the biology of transport mechanisms in parasitic nematodes. We will utilize the pathogenic parasite of livestock, Haemonchus contortus as well as the model nematode Caenorhabditis elegans. Our research will look at regulation of expression, sites of expression and substrate specificity of various transporters. This will be undertaken by analyzing the promoter sequences of Pgp genes, expression of nematode Pgps and determination of their substrate specificity. The electrophysiology of unique nematode ion channels will be investigated, their responses to a range of substrates and anthelmintic drugs, and their expression sites in the nematodes will be determined. Allelic alterations in nematode tubulin proteins, which affect transport and structural functions in nematode cells, and susceptibility to antiparasitic drugs, will be investigated. This novel research will significantly advance in our understanding of transport mechanisms in nematodes and better elucidate the mechanisms of the action of antiparasitic drugs and the mechanisms of drug resistance in nematodes. This knowledge is important to improve parasite control in animals, animal welfare and production.

寄生线虫引起农场动物的疾病、产量损失和死亡，需要使用使用驱虫药物的昂贵控制措施。几乎所有的驱虫剂都靶向线虫的转运机制，表明这些转运机制代表了线虫的独特靶标。例如，驱虫剂如伊维菌素，打开线虫中独特的氯离子通道，导致肌肉麻痹。然而，膜蛋白，如P-糖蛋白（Pgps），可以调节驱虫剂在其作用部位的浓度。了解这些运输系统的功能将推进我们对线虫细胞生理学和药物作用和抗性机制的认识。拟议研究的目标将是进一步阐明寄生线虫运输机制的生物学细节。我们将利用家畜的致病性寄生虫捻转血矛线虫以及模式线虫秀丽隐杆线虫。我们的研究将着眼于各种转运蛋白的表达调控、表达位点和底物特异性。这将通过分析Pgp基因的启动子序列、线虫Pgp的表达和确定其底物特异性来进行。将研究独特的线虫离子通道的电生理学，确定它们对一系列底物和驱虫药物的反应及其在线虫中的表达位点。将研究线虫微管蛋白的等位基因改变，其影响线虫细胞的运输和结构功能，以及对抗寄生虫药物的敏感性。这项新的研究将显着推进我们的理解，在线虫的运输机制，更好地阐明抗寄生虫药物的作用机制和线虫的耐药性机制。这些知识对于改善动物中的寄生虫控制、动物福利和生产非常重要。